This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Objective: To use live-attenuated SIV vaccines as a unique opportunity to study effective anti-immunodeficiency virus immune responses. PROGRESS: We vaccinated eight rhesus macaques with the live-attenuated SIV strain SIVmac239[unreadable]nef in the spring of 2009. We monitored the development of SIV-specific immune responses in this cohort using a variety of assays. The vaccinated animals, along with eight naive controls, were challenged intrarectally (i.r.) with repeated, low doses of the uncloned "swarm" virus SIVsmE660 in the fall of 2009. We detected a significant reduction in acquisition of SIVsmE660 in comparison to na[unreadable]ve controls (Log- rank test;p=0.023). After ten mucosal challenges we detected replication of the challenge strain in only five of the eight vaccinated animals. In contrast, seven of the eight control animals became infected with SIVsmE660 after these ten challenges. Additionally, the SIVsmE660-infected vaccinated animals controlled peak acute virus replication significantly better than the naive controls (Mann-Whitney test;p=0.038). Four of the five SIVsmE660 vaccinees rapidly brought virus replication under control by week 4 post-infection. Unfortunately, two of these four vaccinated animals lost control of virus replication during the chronic phase of infection. Bulk sequencing analysis of the circulating virus in these animals indicated that recombination had occurred between the vaccine and challenge strains and likely contributed to the increased virus replication in these animals. Overall, our results suggest that a well- designed HIV vaccine might both reduce the rate of acquisition and control viral replication. The research used WNPRC Virology &Immunology Services. PUBLICATION: Reynolds MR, Weiler AM, Piaskowski SM, Kolar HL, Hessell AJ, Weiker M, Weisgrau KL, Le[unreadable]n EJ, Rogers WE, Makowsky R, McDermott AB, Boyle R, Wilson NA, Allison DB, Burton DR, Koff WC, Watkins DI. Macaques vaccinated with simian immunodeficiency virus SIVmac239Delta nef delay acquisition and control replication after repeated low-dose heterologous SIV challenge. J Virol. 2010 Sep;84(18):9190-9. Epub 2010 Jun 30. PMID: 20592091, PMCID: PMC2937616.